Neoplasia occurs when normal body cells are changed, proliferating without regard to normal cellular restraints, and invade and colonize areas of the body normally occupied by other cells. See B. Alberts et al., Molecular Biology of the Cell 1255-1294 (3d ed. 1994). According to the American Cancer Society, one-half of American men and one-third of American women will at some point in their lives develop a neoplastic disorder.
Abnormal cell proliferation is usually characterized by an increase rate of division and in some cases uncontrolled growth. One example of a proliferative cell disorder is a tumor or neoplasm. In addition to posing a serious risk in and of themselves, primary malignant neoplasms are particularly problematic given their tendency to invade surrounding tissues and metastasize to distant organs in the body. To date, the most frequently used methods for treating neoplasia, include surgical procedures, radiation therapy, and drug therapies, and combinations of the foregoing. These methods involve significant risk (e.g., of infection, death) to the patient. More importantly, the probability of eliminating all malignant cells is small, particularly if the zone of the malignant growth is not well defined or if the primary tumor has metastasized by the time of surgery. Achieving therapeutic doses effective for treating neoplasm is often limited by the toxic side effects of the anti-cancer agent on normal, healthy tissue. An ideal anti-cancer agent has tissue specificity, thereby reducing side-effects on normal (dividing) cells. There is a need in the art for novel cancer therapeutics which have higher efficacy, specificity, or reduced side effects.
Current antineoplastic drug therapies are administered via a wide variety of routes, and are mostly given orally or by bolus intravenous injection or short infusion, i.e. mostly for up to about 60 minutes. The frequency of the administration generally ranges from once daily to once every week. Other less frequently used modes of administrations include regional intraarterial perfusion, intracavitary, intrathecal, intraventricular, intravesical and topical (Craig et al., Modern pharmacology 4th edition (1994), Little, Brown and Co, page 669-670). In 1994, continuous intravenous infusion was considered investigational (Anderson and Lokich (1994), Oncology, 8(5), p 99-111), with rare exceptions, including 5-FU (Wils (1996), J. Infus. Chemother., vol 6, no 3, 145-148). Intravenous bolus (or short infusion) and continuous infusion (CIV) modes of administration of several drugs were tested and compared and in many cases there was no advantage with CIV administration compared to i.v. bolus administration (Anderson and Lokich, supra).
The compound of Formula I (see below) was disclosed in CA 2,466,340, incorporated by reference in its entirety, and was shown to possess a broad spectrum of anticancer activity by in vitro testing. Both this application and a poster presentation (poster 569, 16th EORTC-NCI-AACR Symposium—Geneva, Sept. 28 to Oct. 1, 2004) disclosed in vivo activity following intraperitoneal administration in glioma mouse models, as well as PK and toxicity profiles including intravenous (IV) bolus, intraperitoneal (IP) and oral (PO) administration. Following the toxicity profile, the AACR poster suggested IV bolus dosing to be the preferred route of administration. The compound was further disclosed in Charan et al. (2004), J. Nat. Prod., vol 67, 1431-1433 as an antimicrobial agent, and in Igarashi et al. (2005), J. Antibiot., vol 58, no 5, 350-352.